Gabapentin is a cyclohexaneacetic acid derivative that is sold under the trademark NEURONTIN for the treatment of partial seizures in adults with epilepsy. The current administration regimen requires 900 to 1800 mgs/day and given in divided doses of three times per day using 300-400 mg capsules. While the drug is highly effective for its prescribed use, there is a need to develop a version of the drug that is administered in a once-a-day regimen and which provides an equally efficacious pharmaceutical product and improved side effect profile.
Gabapentin is 1-(aminomethyl)cyclohexaneacetic acid. This compound is highly soluble in water and in both basic and acidic conditions. The drug per se is not extensively metabolized in humans and is eliminated via renal excretion essentially unchanged. At the typical dosage range (300-600 mgs T.I.D.) the oral bioavailability is approximately sixty percent. The gabapentin elimination half life is five to seven hours and is unaltered by dose or following multiple dosing. Thus, there is a need for an improved product profile that increases bioavailability and provides for a once a day dosing regimen. U.S. Pat. No. 4,087,544 discloses the compound known as gabapentin and various analogs thereof including, for example, the alkyl esters having an R group in place of the carboxylic acid hydrogen wherein R is selected from an alkyl radical containing up to 8 carbon atoms. Specific alkyl groups disclosed include ethyl, methyl and n-butyl. Pharmaceutical compositions and methods of use are also generically disclosed. There is no teaching of therein or reference to the use of any of these compounds in a sustained release formulation. U.S. Pat. No. 5,955,103 discloses certain dosage forms that may contain various active ingredients including gabapentin but it does not disclose or relate to sustained release dosage forms containing pro-drugs of gabapentin. There is a need to combine the advantages of a prodrug of gabapentin and a sustained release delivery system to provide the slow and efficacious delivery of the pro-drug and ultimately the active metabolite of said prodrug-gabapentin.
U.S. Pat. No. 4,595,695 discloses certain prodrugs of valproic acid and describes, for example, the 1xe2x80x2ethoxycarbonyloxyethyl ester of valproic acid. This patent does not disclose or describe gabapentin.
The present invention comprises a prodrug of gabapentin having the formula: 
and the pharmaceutically acceptable salts thereof wherein:
R1 and R2 are independently selected from hydrogen and C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl and substituted versions thereof wherein the substituents are selected from halogen, C1-C6alkyl, hydroxy, alkoxy or carboxy; and
R3 is a variable having the formula xe2x80x94(R4)xe2x80x94Oxe2x80x94(CO)xe2x80x94Oxe2x80x94R5 wherein R4 is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl and substituted versions thereof and R5 is selected from C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl and substituted versions thereof wherein the substituents are selected from C1-C6alkyl, halogen, hydroxy, alkoxy or carboxy.
Alternatively, R3 is selected from C1-C6 alkyl, alkenyl and alkynyl groups or sugars selected from chiral sugars or racemic mixtures and, while certain compounds in this category are not novel per se, the sustained release dosage forms having a compound of formula I wherein R3 is as above are novel and are part of the claimed invention herein. The preferred alkyl group is selected from an ethyl group. Other viable candidates include methyl, propyl, butyl, isobutyl, pentyl, hexyl and other isomers of the alkyl groups and substituted versions thereof wherein the substituents are selected from xe2x80x94NR1R2, halogen, hydroxy, and alkoxy. For example, R3 is selected from 1-(3-propylamine) or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2NH2.
In certain embodiments, the present invention is directed to a compound having the formula (I): 
and the pharmaceutically acceptable salts thereof wherein:
R1 and R2 are independently selected from hydrogen, t-butyloxycarbonyl and C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl and substituted versions thereof wherein the substituents are selected from halogen C1-C6alkyl, hydroxy,alkoxy, or carboxy;
and R3 is a variable having the formula xe2x80x94(R4)xe2x80x94Oxe2x80x94(CO)xe2x80x94Oxe2x80x94R5 wherein R4 is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl and substituted versions thereof and R5 is selected from C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl and substituted versions thereof wherein the substituents are selected from C1-C6alkyl, halogen, hydroxy, alkoxy or carboxy; or
R3 is selected from C1-C6 alkenyl and alkynyl groups or sugars selected from chiral sugars or racemic mixtures thereof and substituted versions thereof wherein the substituents are selected from xe2x80x94NR1R2, halogen, hydroxy, and alkoxy or
R3 is selected from substituted C1-C6alkyl wherein the substituents are selected from xe2x80x94NR1R2, halogen, hydroxy, and alkoxy.
In certain embodiments, the present invention is further directed to a sustained release formulation comprising a compound of formula I wherein R3 is selected from C1-C6 alkyl and substituted versions thereof wherein the substituents are selected from xe2x80x94NR1R2, halogen, hydroxy, and alkoxy and a pharmaceutically acceptable excipient wherein at least one of said excipients provides a sustained release profile relative to the immediate release form of gabapentin or gabapentin analog.
In a preferred embodiment, R1 and R2 are selected from hydrogen; R4 is selected from methylene xe2x80x94(CHxe2x80x94) substituted with CH3 and R5 is selected from C2H5. Thus, the preferred prodrug is the 1xe2x80x2ethoxycarbonyloxyethyl ester of gabapentin and the pharmaceutically acceptable salts thereof or a compound of formula II: 
The present invention also relates to the single enantiomers or diasteroisomers of the prodrugs of formula I when a chiral center or centers is present on the molecule and to pharmaceutical compositions and dosage forms containing such enantiomers or diastereomers. In particular, it is believed that when R3 is a chiral sugar moiety, the different chiral molecules will have different rates of cleavage and metabolism and could provide both immediate release of and sustained release of the cleaved achiral gabapentin molecule.
The present invention further comprises pharmaceutical compositions comprising a compound of formula I or II with the variables described above and a pharmaceutically acceptable excipient.
The present invention also comprises a method of treating patients having seizures comprising administering a pharmaceutically effective amount of a prodrug of formula I or II or a pharmaceutical composition thereof to said patient.
The present invention comprises a dosage form having a compound of formula I or II as the penultimate active ingredient (Prodrug) in the dosage form wherein the compound of formula I or II is converted or metabolized in vivo to gabapentin or a pharmaceutically acceptable salt thereof.
The present invention also comprises a sustained release formulation and dosage form comprising a compound of formula I or II and pharmaceutically acceptable excipients that provide a controlled release of the prodrug and the sustained delivery of the metabolite gabapentin or a salt thereof.
The present invention also relates to a sustained release rate and delivery profile in vitro or in vivo and in the gastric system and in the blood plasma of a patient treated with the prodrug of formula I or II relative to the release rate and delivery profile of gabapentin.